Clinical Projects A. Metformin and longevity In the last decade, research on aging found that metformin use was associated with a reduction in cognitive decline and a longer survival among diabetics compared to those treated with other oral agent. The U.S Food and Drug Administration (FDA) recently approved the first human study to see if an anti-diabetic medication, Metformin, can protect diabetic patients from the multiple diseases from aging. We identified about 300,000 Medicare beneficiaries who were diagnosed with type 2 diabetes post 12/31/2006 and followed them until death, switching to capitated plans, disenrollment from Medicare or 12/31/2016 whichever comes first. During this follow-up, we also collected patients socio-demographic information as well as the use of prescription drugs. Prescription medications include not only 7 commonly prescribed antidiabetics (metformin, insulin, sulfonylulea, thiazolidinedione, GLP-1 analogues, DPP-4 inhibitors, other glucose lowering drugs), but also antihypertensive and lipid-lowering drugs. Controlling for other medication use and patients characteristics in time-varying manner, metformin was not strongly associated with the longer survival (HR=0.95) and the association was not statistically significant. Rather, GLP-1 analogues (newer antidiabetic medication) and lipid-lowering drug (statins) had greater and significant risk reduction effects (HR=0.77 and 0.76 respectively). B. Proton Pump Inhibitors (PPIs) and mortality Proton pump inhibitors (PPIs) have been associated with increases in the incidence of pneumonia, C Decile infection and osteoporosis/fractures, probable chronic renal failure and cardiac events. Xie et al reported that PPIs could also increase the risk of death using Veterans Affairs (VA) data (HR of 1.15 1.25). From 2007-2016 Medicare Parts A, B and D data, we identified 1.2 million Medicare beneficiaries. We also defined a set of covariates: use of PPIs, use of H2 blockers as a control drug, admission to intensive care units or inpatient hospitals, socio-demographics, presence of 58 chronic conditions and treated them as time-dependent covariates in our main analysis of Cox proportion hazard regression. In addition to treating covariates in time-varying manner, we used the concept of lag-time to define drug exposure period in order to control for protopathic bias which occurs when the outcome of interest is associated with an exposure that actually results from early signs and symptoms of the outcome under study. This study is going to be an example of obtaining an accurate estimate of the association between drug exposure and health status. C. Fluoroquinolones and tendon complication Fluoroquinolones (FQ) are among the most widely prescribed antibiotics in the outpatient setting. Several studies have reported the plausible associations between the use of FQs and tendon complications. The U.S FDA issued black box warning labels to FQs since 2008. Several observational studies associate the use of FQ with an increased risk for tendon rupture, aortic aneurysm or dissections (AA/AD). The fact that collagen type I and III fibers provide tensile strength to both tendons and aortic walls, and that FQs can disrupt these fibers in some circumstances, magnify concerns about these reported associations. Some prior studies included amoxicillin as a control drug to determine whether tendon complications are specific to FQs, however, none included azithromycin or cephalexin, the most widely prescribed ingredient antibiotics behind amoxicillin. Further, the associations of FQs with AA/AD could be confounded by visit complaints that stimulate a chest or abdomen imaging exam as well as an antibiotic prescription. Such imaging exams could induce indication bias by revealing incidental aneurysms. In separate analyses, we assessed association of FQ use with the occurrence of a tendon rupture and that of an AA/AD, respectively in a 1.2 million Medicare population using a Cox proportion hazard regression model. In both analyses, we included all three of the other most commonly prescribe antibiotics (Amoxicillin, Azithromycin and Cephalexin) as controls. In the analysis of AA/AD, we also controlled for chest, abdomen and spine imaging exams that were taken within a 30-day from the event date but were not preceded by any antibiotics in the window, thus a confounding not intermediate variable. D. Hormone replacement therapy and Alzheimers disease or dementia Women have Alzheimers disease (AD) or dementia more often than men either due to their longer life expectancy or decline in sex steroid hormone levels around menopause. Hormone replacement therapy (HRT) is an effective treatment for the typical menopause-related symptoms (such as hot flashes, night sweats, irregular periods and etc.) and long-term health problems associated with the menopause (the risk of osteoporosis, cardiovascular disease and stroke). Neuroprotective effects of HRT is controversial: observed in animal studies but not in clinical trials and some observational studies. Initiation of HRT in women over 60 is generally not recommended but is found to be ok for some women after age 65. In this study, we traced about 700,000 female Medicare beneficiaries from Medicare Part D entry to the onset of Alzheimers disease or dementia, death, switching to capitated plan, disenrollment from Medicare, or 12/31/2016 whichever comes first and then we compared the risk of Alzheimers disease or dementia among women treated with HRT to those not treated. Individuals in the study were grouped based on the number of days exposed to HRT (none, less than 6 months, 6-24 months, more than 24 months) and it was treated as a time-dependent covariates in a Cox proportional hazard regression analysis. This study will explore whether or not HRT in women over 65, which is generally not recommended, reduce the risk of Alzheimer's disease or dementia.